Integration of Signaling Cascades in B Cell Development

描述（由申请人提供）：最佳体液应答取决于 激活适当的抗原特异性B细胞，然后 向完全分化的表型的进展，无论是记忆细胞或 浆细胞T细胞在指导这一发育过程中发挥着关键作用， 提供了依赖于接触的信号以及可溶的信号。虽然 CD 4 O/CD 4 OL相互作用以及IL-4在此过程中的关键作用 B细胞整合的分子机制是公认的， 这些不同类别的信号的特征很差。利用 作为一个模型系统，我们已经确定IRF-4作为一个新的 CD 40和IL-4信号转导通路的组成部分。我们有 进一步发现，IRF-4功能可以在特定的阶段进行调制， 通过与Kruppel锌的发育限制集相互作用的方式 指状蛋白我们现在建议，IRF-4在 B细胞活化途径整合和选择性调节 Kruppel锌指蛋白的IRF-4功能对于调节 活化B细胞的发育命运。为了验证这些假设，我们将：1） 剖析控制IRF-4功能的分子机制。2)表征 IRF-4在调节其他CD 4 O/IL-4靶基因中的作用。第三章 研究终末B细胞中IRF-4/Kruppel相互作用的作用 分化完成这些研究将使我们更好地了解 淋巴细胞利用分子机制整合不同的 激活途径。此外，对这些途径的了解可能有助于 选择性靶向特征在于不适当的 淋巴细胞活化

DESCRIPTION (provided by applicant): Optimal humoral responses depend on the activation of the appropriate antigen-specific B cells followed by their progression toward a fully differentiated phenotype, either a memory cell or a plasma cell. T cells play a key role in guiding this developmental program by providing both contact-dependent as well as soluble signals. Although the pivotal roles of the CD4O/CD4OL interaction as well as of IL-4 in this process are well recognized, the molecular mechanisms utilized by B cells to integrate these distinct classes of signals are poorly characterized. Utilizing the regulation of CD23 as a model system, we have identified IRF-4 as a novel component of both CD4O and IL-4 signal transduction pathways. We have furthermore found that IRF-4 function can be modulated in a stage-specific manner by interaction with developmentally restricted sets of Kruppel zinc finger proteins. We now propose that IRF-4 plays a crucial role in the integration of B cell activation pathways and that selective modulation of IRF-4 function by Kruppel zinc finger proteins is critical for regulating the developmental fate of activated B cells. To test these hypotheses we will: 1) Dissect the molecular mechanisms controlling IRF-4 function. 2) Characterize the role of IRF-4 in the regulation of additional CD4O/IL-4 target genes. 3) Investigate the role of the IRF-4/Kruppel interaction during terminal B cells differentiation. Completion of these studies will yield a better understanding of the molecular mechanisms utilized by lymphocytes to integrate distinct activation pathways. Moreover, knowledge of these pathways may allow for selective targeting of pathophysiological states characterized by inappropriate lymphocyte activation.